1. Field of the Invention
The present invention relates to a double chamber container which is particularly suitable for lyophilization, a method of filling the double chamber container, a method of mixing the two components contained therein and the use of the container.
2. Description of the Prior Art
There are pharmaceutical compositions which in their liquid state very rapidly lose their efficacy. To enable these compositions to be used in spite of their short shelf life, special devices and methods of lyophilization have been developed. Thus, pharmaceutical preparations which cannot be used in solution over long periods may be made durable by lyophilization, for example, and possibly stored away from light. The dry substance is only dissolved again, i.e., reconstituted, immediately before use. For this purpose two-component systems have become known for re-dissolving the lyophilizate immediately before use.
As is known, lyophilizates are also used in ready-prepared syringes with two chamber systems, the lyophilizate and solvent being stored separately and only combined just before use. Two-chamber prepared syringes of this kind have already been described in “Die Lyophilisierung von Arzneimitteln in Fertigspritzen”, H. Vetter, Die Pharmazeutische Industrie, Jg. 46, 1984, Nr. 10, S. 1045-1049. Specifically, ready made syringes of this kind are constructed so that each of the components is housed in its own chamber, the chambers being arranged axially one behind the other and only brought into contact with one another immediately before use, so that the liquid component in one chamber can flow into the dry component in the other chamber.
In the prior art, other solutions have been sought for carrying out lyophilization of the solid substance present in the solution using double chamber systems of this kind, to produce a product which can be re-dissolved subsequently or after corresponding storage before use, i.e., to allow the two-component systems to be mixed together, while maintaining the sterility of the two components. The lyophilization of solutions in a syringe is only possible under special conditions, one problem being that during the lyophilization only a very small cross sectional area is available for the exchange of gases. The prior art contains numerous proposals for solving these problems.
The patents and patent applications described in the following paragraphs, namely DE 33 11 525, U.S. Pat. No. 5,788,670, EP 0 718 002 A2, U.S. Pat. No. 4,254,768, and EP 0 295 337 B1 are incorporated herein by reference in their entireties.
For example, a multi chamber disposable syringe is known according to DE 33 11 525, in which the lyophilizate is present in the syringe cylinder, particularly in the first syringe chamber adjacent to the neck of the syringe, which is separated from the second syringe chamber by the syringe plunger. The freeze drying, which is designed particularly for a vessel with a narrow opening, is carried out through two openings, e.g., using a hollow needle passed through the neck of the syringe into the first syringe chamber, this needle being connected to an ice condenser and a vacuum pump, while a second opening in provided through the free annular space between the hollow needle and the neck of the syringe, through which dry gas is passed. Two hollow needles may also be stuck through the elastic plunger body from the rear end of the syringe cylinder and in this way the liquid product in the first syringe chamber can be freeze dried.
According to the disclosure of U.S. Pat. No. 5,788,670, a double chamber syringe which can be broken down into two parts is described, wherein two medicinal components are introduced into the separate cylinders, the medicament in the lower part of the cylinder can be subjected to lyophilization, the two cylinder parts are then sealed and joined together.
Similarly, EP 0 718 002 A2 describes a two-chamber syringe having a syringe cylinder consisting of two part-cylinders. For lyophilization the syringe head can be provided with a closure cap with axially extending recesses which provide a connection to atmosphere in the only partially fitted state. The lyophilization is carried out with a part cylinder. The weak point of such a construction is the connection between the two chambers which, if the seal is inadequate, not only constitutes a possible site of contamination but also means that the liquid substance will run out during the mixing. An additional step is needed to join the two part-cylinders together, and this has to meet extremely stringent requirements. Furthermore, the closure cap has the disadvantage that precise adjustment has to be carried out to ensure that the recesses in the closure cap communicate with the outside, which is not readily possible, as the recesses are covered by the cap, on account of its shape, and therefore it is not easy to tell which position the recesses are in. Furthermore, it is not possible to connect to such a recess, and this may have advantages during lyophilization, for example. The closure also has to be adapted to the particular shape of a syringe head.
According to U.S. Pat. No. 4,254,768 a double chamber syringe also consists of two separate cylinders which can be fitted together. In the upper cylinder a ventilation slot may be provided in the side wall which is closed off when the two cylinders are pushed together and by the provision of an elastomeric ring. The assembly of the two syringe halves has to be carried very precisely, and there is the danger that if the two cylinders are not properly secured against moving relative to one another the venting slot will be exposed again and the system will be unsealed and exposed to contamination. Therefore, particular laborious measures have to be taken to prevent this.
Finally, EP 0 295 337 B1 discloses a double chamber syringe for a solid and liquid medicament, wherein the first lower chamber a towards the head of the syringe contains liquid substance, which is separated by a double ended bypass and a stopper from a second upper chamber b in which a solution can be lyophilized, the wall of the chamber b having a small opening so that the solvent can escape during the lyophilization. A disadvantage of this proposal is that there is a relatively small gap between the opening and the lyophilizate solution, so that when vacuum is applied there is a risk that some of the solution will be expelled from the cylinder. Therefore, the opening is also made correspondingly small, as a result of which much less gas can escape per unit of time. Another problem is that after the lyophilization and sealing the solid is at the top of the double chamber syringe and the liquid is at the bottom, so that the upper stopper is pressed onto the solid, where it will probably remain. After the stopper has been pushed into the double bypass the liquid contained in the lower chamber has to be allowed to move upwards towards the solid in the upper chamber, which is not readily possible. To achieve this, the syringe has to be rotated or shaken repeatedly, for example, in order to rinse the solid out of the upper chamber and force it into the lower chamber where the connection for the injection needle is located. It is impossible to prevent some solid residues remaining on the upper stopper, resulting in incomplete reconstitution.
The disadvantages described above show that there is still a need for an easy to operate device for reliably storing and mixing two-component systems, of which one component is a solid, particularly a lyophilizate, and the other is a dissolving/dispersing medium therefor. In particular it should be possible to carry out lyophilization directly in the device, while avoiding the disadvantages of the prior art. Contamination from outside should be ruled out as far as possible. In particular, subsequent mixing should take place without removing the components from the sterile inner part of the device and without any external intervention in the system thereby compromising the sterile condition. The device should also be easy to store. Furthermore, a method of easily filling a device of this kind should be provided. The device and the method should be usable on an industrial scale.